| Article ID | Journal | Published Year | Pages | File Type |
|---|---|---|---|---|
| 1368970 | Bioorganic & Medicinal Chemistry Letters | 2015 | 7 Pages |
Abstract
Our investigation of the structure–activity and structure–liability relationships for dihydropyrrolopyrazol-6-one MCHR1 antagonists revealed that off-rate characteristics, inferred from potencies in a FLIPR assay following a 2 h incubation, can impact in vivo efficacy. The in vitro and exposure profiles of dihydropyrrolopyrazol-6-ones 1b and 1e were comparable to that of the thienopyrimidinone counterparts 41 and 43 except for a much faster MCHR1 apparent off-rate. The greatly diminished dihydropyrrolopyrazol-6-one anti-obesity response may be the consequence of this rapid off-rate.
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Physical Sciences and Engineering
Chemistry
Organic Chemistry
Authors
Pratik Devasthale, Wei Wang, Andres S. Hernandez, Fang Moore, Kishore Renduchintala, Radhakrishnan Sridhar, Mary Ann Pelleymounter, Daniel Longhi, Ning Huang, Neil Flynn, Anthony V. Azzara, Kenneth Rohrbach, James Devenny, Suzanne Rooney, Michael Thomas,